Black is white, up is down and short is long,
And everything you thought was just so
important doesn't matter
Everything you know is wrong,
Just forget the words and sing along,
All you need to understand is
Everything you know is wrong
- Wierd Al Yankovic

Thursday, September 23, 2010

You Neanderthal!

Neanderthals mated with some modern humans after all and left their imprint in the human genome, a team of biologists has reported in the first detailed analysis of the Neanderthal genetic sequence.

The biologists, led by Svante Paabo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, have been slowly reconstructing the genome of Neanderthals, the stocky hunters that dominated Europe until 30,000 years ago, by extracting the fragments of DNA that still exist in their fossil bones. Just last year, when the biologists first announced that they had decoded the Neanderthal genome, they reported no significant evidence of interbreeding.

Scientists say they have recovered 60 percent of the genome so far and hope to complete it. By comparing that genome with those of various present day humans, the team concluded that about 1 percent to 4 percent of the genome of non-Africans today is derived from Neanderthals. But the Neanderthal DNA does not seem to have played a great role in human evolution, they said.

Experts believe that the Neanderthal genome sequence will be of extraordinary importance in understanding human evolutionary history since the two species split some 600,000 years ago.

So far, the team has identified only about 100 genes — surprisingly few — that have contributed to the evolution of modern humans since the split. The nature of the genes in humans that differ from those of Neanderthals is of particular interest because they bear on what it means to be human, or at least not Neanderthal. Some of the genes seem to be involved in cognitive function and others in bone structure.

“Seven years ago, I really thought that it would remain impossible in my lifetime to sequence the whole Neanderthal genome,” Dr. Paabo said at a news conference. But the Leipzig team’s second conclusion, that there was probably interbreeding between Neanderthals and modern humans before Europeans and Asians split, is being met with reserve by some archaeologists.

A degree of interbreeding between modern humans and Neanderthals in Europe would not be greatly surprising given that the species overlapped there from 44,000 years ago when modern humans first entered Europe to 30,000 years ago when the last Neanderthals fell extinct. Archaeologists have been debating for years whether the fossil record shows evidence of individuals with mixed features.

But the new analysis, which is based solely on genetics and statistical calculations, is more difficult to match with the archaeological record. The Leipzig scientists assert that the interbreeding did not occur in Europe but in the Middle East and at a much earlier period, some 100,000 to 60,000 years ago, before the modern human populations of Europe and East Asia split. There is much less archaeological evidence for an overlap between modern humans and Neanderthals at this time and place.

Dr. Paabo has pioneered the extraction and analysis of ancient DNA from fossil bones, overcoming daunting obstacles over the last 13 years in his pursuit of the Neanderthal genome. Perhaps the most serious is that most Neanderthal bones are extensively contaminated with modern human DNA, which is highly similar to Neanderthal DNA. The DNA he has analyzed comes from three small bones from the Vindija cave in Croatia.

“This is a fabulous achievement,” said Ian Tattersall, a paleontologist at the American Museum of Natural History in New York, referring to the draft Neanderthal genome that Dr. Paabo’s team describes in Thursday’s issue of Science.

But he and other archaeologists questioned some of the interpretations put forward by Dr. Paabo and his chief colleagues, Richard E. Green of the Leipzig institute, and David Reich of Harvard Medical School. Geneticists have been making increasingly valuable contributions to human prehistory, but their work depends heavily on complex mathematical statistics that make their arguments hard to follow. And the statistical insights, however informative, do not have the solidity of an archaeological fact.

“This is probably not the authors’ last word, and they are obviously groping to explain what they have found,” Dr. Tattersall said.

Richard Klein, a paleontologist at Stanford, said the authors’ theory of an early interbreeding episode did not seem to have taken full account of the archaeological background. “They are basically saying, ‘Here are our data, you have to accept it.’ But the little part I can judge seems to me to be problematic, so I have to worry about the rest,” he said.

In an earlier report on the Neanderthal genome, the reported DNA sequences were found by other geneticists to be extensively contaminated with human DNA. Dr. Paabo’s group has taken extra precautions but it remains to be seen how successful they have been, Dr. Klein said, especially as another group at the Leipzig institute, presumably using the same methods, has obtained results that Dr. Paabo said he could not confirm.

Dr. Paabo said that episode of human-Neanderthal breeding implied by Dr. Reich’s statistics most plausibly occurred “in the Middle East where the first modern humans appear before 100,000 years ago and there were Neanderthals until 60,000 years ago.” According to Dr. Klein, people in Africa expanded their range and reached just Israel during a warm period some 120,000 years ago. They retreated during a cold period some 80,000 years ago and were replaced by Neanderthals. It is not clear whether or not they overlapped with Neanderthals, he said.

These humans, in any case, were not fully modern and they did not expand from Africa, an episode that occurred some 30,000 years later. If there was any interbreeding, the flow of genes should have been both ways, Dr. Klein said, but Dr. Paabo’s group sees evidence for gene flow only from Neanderthals to modern humans.

The Leipzig group’s interbreeding theory would undercut the present belief that all human populations today draw from the same gene pool that existed a mere 50,000 years ago. “What we falsify here is the strong out-of-Africa hypothesis that everyone comes from the same population,” Dr. Paabo said.

In his and Dr. Reich’s view, Neanderthals interbred only with non-Africans, the people who left Africa, which would mean that non-Africans drew from a second gene pool not available to Africans.

A decade after scientists first cracked the human genome, researchers announced in the May 7 issue of Science that they have done the same for Neanderthals, the species of hominid that existed from roughly 400,000 to 30,000 years ago, when their closest relatives, early modern humans, may have driven them to extinction.

Led by ancient-DNA expert Svante Pääbo of Germany's Max Planck Institute for Evolutionary Anthropology, scientists reconstructed about 60% of the Neanderthal genome by analyzing tiny chains of ancient DNA extracted from bone fragments of three female Neanderthals excavated in the late 1970s and early '80s from a cave in Croatia. The bones are 38,000 to 44,000 years old.

The genetic information turned up some intriguing findings, indicating, for instance, that at some point after early modern humans migrated out of Africa, they mingled and mated with Neanderthals, possibly in the Middle East or North Africa as much as 80,000 years ago. If that is the case, it occurred significantly earlier than scientists who support the interbreeding hypothesis would have expected.

Comparisons with DNA from modern humans show that some Neanderthal DNA has survived to the present. Moreover, by analyzing ancient DNA alongside modern samples, the team was able to identify a handful of genetic changes that evolved in modern humans sometime after their ancestors and Neanderthals diverged, 440,000 to 270,000 years ago.

The process of sequencing was painstaking. Among the challenges were eliminating bacterial and fungal DNA, which accounted for 97% of the genetic material in the samples, and guarding against contamination from the researchers, whose DNA might be mistaken for Neanderthals'. Plus, the DNA was so fragmented that the chains were often no longer than 40 or 50 base pairs. "We used half a gram of bones to produce the 3 billion base pairs," Pääbo said in a May 5 press conference. "I really thought until six or seven years ago that it would remain impossible, at least for my lifetime, to sequence the entire genome." New sequencing technologies made it feasible, he said.

Researchers compared the Neanderthal genome with the genomes of five living people: one San from southern Africa, one Yoruba from West Africa, one Papua New Guinean, one Han Chinese and one French person. Scientists discovered that 1% to 4% of the latter three DNA samples is shared with Neanderthals — proof that Neanderthals and early modern humans interbred. The absence of Neanderthal DNA in the genomes of the two present-day Africans indicates that interbreeding occurred after some root population of early modern humans left Africa but before the species evolved into distinct groups in Europe and Asia.

The gene flow of Neanderthal DNA into early human DNA was found in only one direction: from Neanderthals to us. The study found no early modern human DNA in the Neanderthal genome. It is not clear whether interbreeding happened a few times among small populations or frequently among large populations; the genetic remnants would look the same with current technology. The Neanderthal DNA appears in the modern human genomes randomly, suggesting it offers no evolutionary benefit and is merely a genetic relic.

Finding any mixture of DNA was a surprise to the team. "We came into the project extremely biased against the idea of gene flow," said Harvard Medical School's David Reich, one of the study's authors, who specializes in examining the relationship between human populations using genomic data.

Still, other paleoanthropologists say the discovery is not entirely unexpected. There is ample archaeological evidence — including tools, habitation sites and fossils — that Neanderthals and early modern humans may have coexisted in the Middle East as much as 80,000 years ago, and certainly in Europe 30,000 to 45,000 years ago. What has been missing until now is the genetic evidence.

"The fact that they found it across the board says that the evidence must be very widespread across modern humans," says Erik Trinkaus, an anthropologist at Washington University in St. Louis, Mo., who has long argued that the human fossils he has studied in France, Romania, the Czech Republic and other places show mixed ancestry. "If you can find evidence [of Neanderthals] after 30,000 years of [human] genetic shifting, then it must have been pretty important or prominent then." Trinkaus speculates that the genetic flow between Neanderthals and early modern humans might have been as high as 10% to 20%.

The new finding may prompt a tweaking of the well-known Out of Africa theory, which in its strictest interpretation says a small group of early modern humans left Africa and outcompeted and replaced all other hominids without any interbreeding. The alternate theory, known as multiregionalism, argues that distinct populations of modern humans developed simultaneously around the world and along the same evolutionary lines by swapping genes.

"What we falsify here is the very hard Out of Africa theory," said Pääbo. "We show that outside Africa there is this 1% to 4% that came from archaic humans. Of course, it's totally possible that archaic forms that we don't know contributed to Africans today. I don't think we should take this as evidence that only people outside Africa have some 'caveman' biology within them."

According to Trinkaus, many paleoanthropologists have long believed that early modern humans and Neanderthals interbred. "People have been saying this for decades," he argues. "The minority position was the position that there was no gene flow. Most people who work with the fossil record support some level of admixture."

Whatever our mixing, it is human uniqueness that has also been revealed by the sequencing. By comparing the Neanderthal genome with those of modern humans, the team identified a small number of genetic changes that were newly evolved in modern humans. Some of the changes may have arisen as a result of genetic drift, but others seem to have been positively selected for — meaning they swept through populations rapidly, possibly because they gave us some advantage.

The genes in which some of the changes occurred play a role in cognitive and physical development — such as cranial features, skin pigmentation and how we metabolize energy. The study's authors don't yet know what the specific changes signify, but in living people, mutations in some of the genes related to cognitive development contribute to conditions such as Down syndrome, schizophrenia and autism.

Despite the lingering questions, the sequencing of the genome is itself a triumph. "Sequencing ancient human DNA is extremely difficult," says computational biologist Webb Miller, part of a Penn State team that sequenced the genome of a woolly mammoth in 2008 — the first such analysis of an extinct animal. (For this achievement, Miller and colleague Stephan Schuster were included among the TIME 100 honorees in 2009.)While his own work was a technological breakthrough, "what they did was harder," Miller says. "We were working with a frozen sample, so we could get a lot more DNA from the sample. What they did technically was extremely difficult and full of land mines. And I hope they didn't hit any."

Miller adds, "This is a way cool paper. I think it's really fascinating. Some [scientists] will love it, and some of them will hate it. It's great science."